4.1. Therapeutic indications

ClinOleic 20% is indicated as a source of calories and essential fatty acids for patients requiring parenteral nutrition.

4.2. Posology and method of administration

The emulsion is for administration by intravenous infusion as part of a parenteral nutrition regimen.

Posology

The posology depends on energy expenditure, the patient's clinical status, body weight, and ability to metabolize ClinOleic 20%, as well as additional energy given orally/enterally. Therefore, the dosage should be individualized and the bag size chosen accordingly.

The maximum daily dose of ClinOleic 20% should be based on individual total nutritional requirements and patient tolerance.

Adult patients

Up to 60% of the energy requirements of the patient can be provided by ClinOleic 20%.

The infusion should be started at a rate of 0.5ml per minute for the first 15-30 minutes. The rate can then be increased to allow 500ml of ClinOleic 20% to be administered on the first day. On subsequent days the dose may be increased to a maximum of 2.5g lipids/kg of body weight with a maximum infusion rate of 0.25g lipids/kg/hour.

Paediatric patients

Up to 60% of the energy requirements of the patient can be provided by ClinOleic 20%.

The infusion should be started at a rate of 0.05ml per minute for the first 10-30 minutes. Never exceed an infusion rate of 0.25g lipids/kg/hour. The daily dosage should not exceed 4g lipids/kg of body weight.

In small for gestational age or premature infants with impaired capacity to metabolise fat, initial dosage should be 0.5g lipids/kg/day. This dosage can be increased daily by 0.25g lipids/kg/day up to a maximum dose of 3g lipids/kg/day.

Intravenous fat clearance must be monitored closely every day. In the absence of monitoring of serum triglycerides, the dosage should not exceed 2g lipids per kg body weight in 24 hours.

Method of administration

Intravenous infusion:

• When administered as part of a complete nutrition admixture (with glucose and amino acids) the central or peripheral venous route should be chosen depending on the osmolarity of the final admixture.

• When used in neonates and children below 2 years, the solution (in bags and administration sets) should be protected from light exposure until administration is completed (see section 4.4, 6.3 and 6.6).

• In rare cases, when infused alone as a complementary support to oral or enteral nutrition, ClinOleic 20% can be administered via central or peripheral vein.

It is recommended that after opening the bag, the contents should be used immediately, and should not be stored for a subsequent infusion.

The recommended duration of infusion for a parenteral nutrition bag is between 12 and 24 hours, depending on the clinical situation.

The administration flow rate must be adjusted taking into account the dose being administrated, the daily volume intake, and the duration of the infusion (see Section 4.9).

Treatment with parenteral nutrition may be continued for as long as it is justified by the clinical situation of the patient.

Usage in nutritive admixtures (with glucose and amino acids)

Before administration to the patient, the compatibility of the components and stability of the admixture must be checked. Admixing should be accompanied by gentle agitation during preparation under strict aseptic conditions.

4.3. Contraindications

The use of ClinOleic is contra-indicated in the following situations:

– hypersensitivity to egg protein, soya protein or peanut protein or to any of the active substances or excipients.

- severe hyperlipidaemia and severe disorders of lipid metabolism characterised by hypertriglyceridemia. Lipoid nephrosis and acute pancreatitis if accompanied by hyperlipaemia.

4.4. Special warnings and precautions for use

WARNINGS

The infusion must be stopped immediately if any abnormal signs or symptoms of an allergic reaction (such as sweating, fever, shivering, headache, skin rashes or dyspnoea) develop. This medicinal product contains soya-bean oil and egg phospholipids. Soybean and egg proteins may cause hypersensitivity reactions. Cross-allergic reactions between soybean and peanut proteins have been observed.

Infection and sepsis complications

Patients who require parenteral nutrition are often predisposed to infectious complications due to malnutrition and/or their underlying disease state. Infection and sepsis may occur as a result of the use of intravenous catheters to administer parenteral formulations, or poor maintenance of catheters and contaminated solutions. Immunosuppression and hyperglycemia may predispose patients to infectious complications.

The occurrence of septic complications can be decreased with heightened emphasis on aseptic technique in catheter placement and maintenance, as well as aseptic technique in the preparation of the nutritional formula. Careful monitoring of signs, symptoms, and laboratory test results (including fever, chills, leukocytosis, and hyperglycaemia), and frequent checks of the access device for technical complications can help recognize early infections.

Hepatic Insufficiency

Use with caution in patients with hepatic insufficiency. Regular clinical and laboratory tests are required, particularly blood glucose, electrolytes and triglycerides (not exceeding 3 mmol/L during infusion).

Haematologic and thrombophlebitis

Use with caution in patients with coagulation disorders and anaemia. Blood count and coagulation parameters should be closely monitored

Thrombophlebitis may develop, particularly if peripheral veins are used. The catheter insertion site must be monitored daily for local signs of thrombophlebitis.

“Fat overload syndrome” may be caused by overdose and/or infusion rate higher than recommended. However, the signs and symptoms of this syndrome may also occur when the product is administered according to instructions, e.g. in patients with reduced or limited ability to metabolize the lipids contained in CLINOLEIC 20%. This syndrome is associated with a sudden deterioration in the patient's clinical condition and is characterized by findings such as fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, liver fatty infiltration (hepatomegaly), deteriorating liver function, and central nervous system manifestations (e.g., coma). The syndrome is usually reversible when the infusion of the lipid emulsion is stopped. Serious adverse reactions including acute respiratory distress and metabolic acidosis have been reported in neonates and infants after rapid infusion of intravenous lipid emulsions. ClinOleic 20% is administered as part of a parenteral nutrition regimen. Refeeding severely undernourished patients with parenteral nutrition may result in the refeeding syndrome. The syndrome is characterized by the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop. Careful monitoring and slowly increasing nutrient intakes, while avoiding overfeeding, can prevent these complications.

Patients at risk of refeeding syndrome include those with anorexia nervosa, chronic malnutrition (due to age or carcinoma), chronic alcoholism, prolonged fasting, or postoperative patients.

Baxter has not performed any compatibility studies of additions made directly to the Clinoleic 20% emulsion container. Destabilization of the lipid emulsion may result from such additions. If admixture into the Clinoleic 20% emulsion container is deemed necessary, insure that additives are compatible with the emulsion. Any additions to the container should be performed under strict aseptic conditions.

If ClinOleic 20% is mixed with glucose and/or amino acid solutions, the compatibility should be checked before administration (see Sections 6.2 and 6.6). Formation of precipitates could result in microvascular pulmonary emboli.

PRECAUTIONS

As for any parenteral infusion, particular attention should be given on monitoring fluid status, especially in patients with acute oliguria or anuria and in patients with pulmonary oedema or heart failure.

Severe water and electrolyte equilibration disorders, severe fluid overload states, and severe metabolic disorders must be corrected before starting the infusion.

Fat emulsions should be administered simultaneously with carbohydrates and amino acids to avoid occurrence of metabolic acidosis.

The blood sugar, serum triglycerides, the acid-base balance, electrolytes, serum osmolarity, kidney function, coagulation parameters and the blood count must be checked at regular intervals.

Parenteral nutrition should be used with caution in patients with pre-existing liver disease or liver insufficiency. Liver function parameters should be closely monitored in these patients (see below).

Parenteral Nutrition Associated Liver Diseases (PNALD) including cholestasis, hepatic steatosis, fibrosis and cirrhosis, possibly leading to hepatic failure, as well as cholecystitis and cholelithiasis are known to develop in some patients on parenteral nutrition. The etiology of these disorders is thought to be multifactorial and may differ between patients. Patients developing abnormal laboratory parameters or other signs of hepatobiliary disorders should be assessed early by a clinician knowledgeable in liver diseases in order to identify possible causative and contributory factors, and possible therapeutic and prophylactic interventions.

Light exposure of solutions for intravenous parenteral nutrition, especially after admixture with trace elements and/or vitamins, may have adverse effects on clinical outcome in neonates, due to generation of peroxides and other degradation products. When used in neonates and children below 2 years, ClinOleic 20% should be protected from light until administration is completed (see sections 4.2, 6.3 and 6.6).

4.5. Interaction with other medicinal products and other forms of interaction

Complete information about interactions is not available.

No interaction studies have been performed with ClinOleic 20%. If it is necessary to introduce medications, verify the compatibility and mix thoroughly before administration to the patient.

Olive and soybean oils have a natural content of vitamin K1, that may counteract the anticoagulant activity of coumarin derivatives, including warfarin.

The lipids contained in this emulsion may interfere with the results of certain laboratory tests if the blood sample is taken before the lipids are eliminated.

4.6. Fertility, pregnancy and lactation

There is no adequate data from the use of ClinOleic 20% in pregnant and lactating women. Physicians should carefully consider the potential risks and benefits for each specific patient before prescribing ClinOleic 20%.

4.7. Effects on ability to drive and use machines

Not applicable.

4.8. Undesirable effects

Adverse drug reactions (ADRs) that occurred after administration of ClinOleic 20% in clinical trials and those from post-marketing reports are presented. ClinOleic was administered to 274 adult patients in the clinical trials. The most frequent ADRs noted for ClinOleic 20% in clinical trials were nausea/vomiting, which occurred in more than 2% of the patients.

Frequencies of ADRs are presented using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); and unknown (cannot be estimated from the available data).

Clinical Trial and Post-Marketing Adverse Drug Reactions Reported for ClinOleic 20%

System Organ Class (SOC)

MedDRA Preferred Term

Frequency

BLOOD AND LYMPHATIC SYSTEM DISORDERS

Leukopaenia

Thrombocytopaenia

Uncommon

Unknown

IMMUNE SYSTEM DISORDERS

Hypersensitivity

Unknown

METABOLISM AND NUTRITION DISORDERS

Hyperglycaemia

Hypoproteinaemia

Hyperlipidaemia†

Common

Common

Common

VASCULAR DISORDERS

Mean arterial pressure decreased

Circulatory collapse

Hypotension

Hot flush

Common

Uncommon

Uncommon

Uncommon

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

Dyspnoea

Uncommon

GASTROINTESTINAL DISORDERS

Nausea /Vomiting

Abdominal distension

Abdominal pain

Epigastric discomfort

Common

Common

Uncommon

Uncommon

HEPATOBILIARY DISORDERS

Cholestasis

Cytolytic hepatitis

Cholecystitis

Cholelithiasis

Common

Uncommon

Unknown

Unknown

MUSCULOSKELETAL AND CONNECTIVE TISSUE AND BONE DISORDERS

Muscle spasms

Back pain

Common

Uncommon

SKIN AND SUBCUTANEAOUS DISORDERS

Pruritus

Unknown

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

Chills

Uncommon

INVESTIGATIONS

Blood bilirubin increased**

Liver function test abnormal‡

Pancreatic enzyme increased

Blood triglycerides increased

Common

Common

Uncommon

Common

†includes reports of Hypertriglyceridemia

‡includes reports of Hepatic Function Abnormal, Hepatic Enzyme Increased, Blood Alkaline Phosphatase Increased, Gamma Glutamyl Transferase Increased, Blood Alkaline Phosphatase Abnormal, Gamma Glutamyl Transferase Abnormal

** Includes Bilirubin Conjugated Increased

Fat overload syndrome (very rare): see section 4.4 for more information.

During long-term parenteral nutrition, the following adverse reactions have been observed:

- increase of alkaline phosphatase, transaminases and bilirubin,

- rarely: hepatomegaly and icterus,

- moderate thrombocytopenia.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.Website: www.mhra.gov.uk/yellowcard

4.9. Overdose

In the event of fat overload (severe hyperlipidaemia, hepatosplenomegaly with hepatic dysfunctions, thrombocytopenia and respiratory failure) during therapy, stop or if necessary, continue at a reduced dosage the infusion of ClinOleic 20% until plasma triglyceride concentration has returned to baseline. In neonates and infants, an overdose and/or increased infusion rate may cause serious adverse events such as metabolic acidosis and respiratory distress. These effects are usually reversible after the lipid infusion is stopped (see section 4.4 and 4.8).